Integrated 18FDG PET/CT: Utility and Applications in Clinical Oncology

Accurate diagnosis and staging are essential for an optimal management of cancer patients. Positron emision tomography with 2-deoxy-2-fluorine-18-fluoro-D-glucose (18FDG-PET) and, more recently, 18FDG-PET/computed tomography (18FDG-PET/CT) have emerged as powerful imaging tools in oncology, because of the valuable functional information they provide. The combined acquisition of PET and CT has synergistic advantages over its isolated constituents and minimizes their limitations. It decreases examination times by 25%–40%, leads to a higher patient throughput and unificates two imaging procedures in a single session. There is evidence that 18FDG-PET/CT is a more accurate test than either of its components for the evaluation of various tumors. It is a particularly valuable tool for detection of recurrence, especially in asymptomatic patients with rising tumor markers and those with negative or equivocal findings on conventional imaging tests. Yet, there are some limitations and areas of uncertainty, mainly regarding the lack of specificity of the 18FDG uptake and the variable 18FDG avidity of some cancers. This article reviews the advantages, limitations and main applications of 18FDG-PET/CT in oncology, with especial emphasis on lung cancer, colorectal cancer, lymphomas, melanoma and head and neck cancers.


Introduction
Cancer is one of the leading causes of death worldwide. Accurate diagnosis, staging and restaging are essential for an adequate therapeutic management of these patients. Conventional imaging techniques, such as computed tomography (CT) and magnetic resonance rely on anatomic alterations and abnormal contrast enhancement, with limitations to detect infi ltration in normal-sized structures and characterization of residual lesions. Positron emision tomography (PET) with 2-deoxy-2-fl uorine-18-fl uoro-Dglucose ( 18 FDG), an analogue of glucose, provides valuable functional information based on the increased glucose uptake and glycolysis of cancer cells. Therefore, PET has the ability to depict metabolic abnormalities before morphologic alterations occur. The main drawback of PET is the limited spatial resolution which impedes precise localization of foci of 18 FDG uptake and hinders identifi cation of lesions adjacent to organs with physiological 18 FDG uptake (urinary tract, bowel) (Shreve et al. 1999). In addition, 18 FDG is physiologically taken up by various organs and also by sites of infl ammation. The hybrid PET/CT modality acquires PET and CT data in the same imaging session and allows accurate anatomic localization of the lesions detected on the 18 FDG-PET scan. Since its introduction integrated PET/CT has rapidly gained clinical acceptance and, in the last decade it has become an important imaging tool in clinical oncology.
In this article, we review the advantages, limitations, clinical utility, and main applications of combined 18 FDG-PET/CT in oncology.

Advantages of combined 18 FDG-PET/CT
There are several advantages of combined PET/CT over its isolated constituents, that translate into highly synergistic benefi ts in the management of a variety of cancers.

Technical advantages
From a technical point of view, the use of CT data photon attenuation correction instead of data from an external radioactive transmission source results in a much faster PET image acquisition, decreasing examination times by 25%-40% relative to standalone PET (Hany et al. 2002;von Schulthess et al. 2006). Straightforward consequences are a higher patient throughput and a more effi cient use of the fast-decaying PET radiopharmaceutical (Hany et al. 2002). In addition, owing to the high photon fl ux used for CT attenuation correction the noise is reduced and the image quality of the PET scan is improved (Carney et al. 2003).

Clinical advantages
For the patient, the decreased scan time and unification of the two imaging procedures in a single session, performing preparation such as fasting only once, lead to a greater patient comfort and convenience.
The most remarkable clinical advantage of the integrated PET/CT is the accurate co-registration of metabolic and anatomic data, providing improved lesion localization and characterization, which results in a signifi cant reduction of falsepositive and false-negative fi ndings, and increased diagnostic and staging accuracy of numerous cancers as compared with either modality (Charron et al. 2000;Hany et al. 2002;Israel et al. 2002;Antoch et al. 2003; Bar-Shalom et al. 2003, Bristow et al. 2003Czernik et al. 2003). In general, the CT component adds mainly specifi city, whereas PET adds mostly sensitivity. Thus, the combined PET/CT is a more sensitive and specifi c test than either of its constituents obtained separately (von Schulthess et al. 2006). Other benefi ts of PET/CT include identifi cation of small lesions that might be overlooked on either PET or CT alone, normalsized malignant nodes (Fig. 1), confi dent characterization of suspicious or equivocal fi ndings on other imaging techniques, and biopsy guidance. In addition, the gathered functional and anatomic data are integrated by the interpreting physicians in a single report, with a diagnostic impression formulated from the combination of both techniques, that facilitates the transfer of diagnostic information to the referring physicians. It must be noted that the quality of the CT component is variable depending on the institution and clinical indication for PET/ CT. Hence, the PET/CT report should specify whether the CT scan was performed with a very low current (such as 10 mAs) or low current (40-80 mAs) for attenuation correction and anatomic localization only, or with full dose for diagnostic purposes, and the use of contrast agents, to decide the need for further morphologic imaging. In addition, because of the synergistic benefi ts of the combined acquisition of both modalities, the administration of intravenous contrast material can be eliminated for certain indications (e.g. monitoring response to therapy) (Wong et al. 2007). These benefi tial aspects of PET/CT potentially improve the management of cancer patients.

Limitations and pitfalls of combined 18 FDG-PET/CT
There are potential pitfalls of PET/CT related to technical factors. Patient motion during imaging acquisition may produce misregistration on the fused images and cause confusion or mistakes regarding the correct localization of the 18 FDG uptake (Kapoor et al. 2004). Although patient movement and breathing motion can be minimized by placing the patient in a comfortable position and acquiring CT in normal expiration, some artifacts caused by respiratory, cardiac or bowel motion are unavoidable. These mismatchs are readily identifi ed by carefully reviewing both sets of images, and usually do not create diagnostic dilemmas. A drawback of acquiring the CT in expiratoty phase instead of instead of full inspiration is that the chest images show, compared with diagnostic thoracic CT scans, lower lung volumes and more dependent atelectasis and ground-glass opacities that potentially obscure small nodules. Even though, the chest images of PET/CT are usually of an adequate quality for most of the oncologic indications (Wong et al. 2007). In selected cases an additional inspiratory thoracic CT can be performed after the acquisition of PET/CT in expiration. Attenuation correction artifacts that may occur with high-density elements such as metallic devices are easily recognized on uncorrected PET images, which are always available.
Limitations of 18 FDG-PET/CT in the evaluation of cancer have been documented as well. 18 FDG is not a cancer-specifi c tracer and accumulates in areas of increased metabolism such as several normal organs (brain, salivary glands, vocal cords, myocardium, urinary tract), and brown fat. Although the better anatomic localization and morphologic information of 18 FDG-PET/CT improves the diagnostic accuracy compared to PET standalone, in occasions, tumor detection may be impaired in these structures, even on 18 FDG-PET/ CT. In this regard, relatively small brain metastases can be missed on 18 FDG-PET/CT owing to the high background activity. Hence, symptomatic patients with negative scans or those at high risk for brain metastases will require further imaging with MRI or contrast-enhanced CT. 18 FDG is also taken up by activated leukocytes and macrophages, resulting in enhanced uptake in sites of active infl ammation and tissue repair (infection, sarcoidosis, vasculitis, post-radiotherapy and post-surgery changes, etc) (Fig. 2). The fi ndings on the CT component may facilitate the interpretation of 18 FDG-avid lesions, e.g. the morphologic changes secondary to a bone fracture. However, exclusion of malignancy may be impossible based on 18 FDG-PET/CT images only, and correlation with clinical data is essential to the correct interpretation of scans. In addition, a variety of benign tumors in the head and neck and colonic adenomas may exhibit an increased uptake.
On the other hand, there are limitations related to the variability in 18 FDG uptake of several types of cancers. Well-differentiated, hypo-cellular and mucin-producing tumors (and their metastases), such as bronchioalveolar carcinoma, hepatocellular carcinoma and intraductal papillary mucinous tumor exhibit low 18 FDG uptake (Berger et al. 2000) (Fig. 3). Yet, this limitation of 18 FDG-PET/ CT may be valuable in certain cases, as the degree of 18 FDG uptake may be correlated with the  biological aggresiveness with a prognostic signifi cance, and help to select therapies (Yang et al. 2005).

Clinical utility
18 FDG PET/CT has proven effective for diagnosis and staging of various cancers (Beyer et al. 2000), especially non-small-cell lung carcinoma (NSCLC), lymphoma, recurrent colorectal carcinoma, melanoma and sarcomas. Recently, especial attention has been focused on restaging and monitoring tumor response, where this technique is probably most useful (Oriuchi et al. 2006). 18 FDG PET/CT is a valuable tool for detection of recurrence, particularly in asymptomatic patients with rising levels of tumor markers and also in patients with negative or equivocal fi ndings on conventional imaging tests. In patients with residual masses after therapy completion or with post-surgical or postradiation anatomic distortion, 18 FDG PET/CT allows accurate differentiation between viable tumor and necrosis or scar. With its precise anatomic correlation, it may be used to direct diagnostic biopsy to the specifi c site of 18 FDG uptake to obtain tissue confi rmation of recurrence. Thus, relapses can be early detected and treated, while tumoral burden is still low. Conversely, exclusion of recurrence in areas of post-therapy morphologic abnormalities avoids unnecessary diagnostic procedures and treatments. However, studies performed within 2-3 months of radiation or 1-2 months of surgery may yield false-positive fi ndings, as post-therapeutic inflammation causes 18 FDG uptake (Hojgaard et al. 2007;Oriuchi et al. 2006;Von Schulthess et al. 2006).
Because metabolic changes in a tumor precede size reduction, 18 FDG PET/CT is effective for assessment of response to therapy. Successful chemotherapy decreases cellular glucose transport and glycolysis and, hence, tumor uptake of 18 FDG. It has been reported that a decrease in 18 FDG uptake may be observed as early as 1-2 weeks after the fi rst cycle of effective chemotherapy  (Brun et al. 2002;Kostakoglu et al. 2002;Weber et al. 2003). In this way, 18 FDG PET/CT enables early identifi cation of non-responders and a change in therapy.
Available information in the literature on the impact of 18 FDG PET/CT on radiotherapy treatment planning is limited (Van Baardwijk et al. 2006;Greco et al. 2007). However, current data suggest an improvement in target volume delineation. In this way, 18 FDG PET/CT may modify radiotherapy fi elds to reduce radiation dose to normal tissues and allow selective dose escalation to hypermetabolic areas within the tumoral mass. The advantages of 18 FDG PET/CT seem to be more relevant in lung cancer, enabling differentiation between tumor and atelectasis and detection of unsuspected metastatic lymph nodes, and in head and neck carcinomas, where a better delineation of involved sites may reduce sequelae of radiation. Further research is needed to determine the exact role of 18 FDG PET/CT in radiotherapy treatment planning, however.

Radiation dose
There is some concern regarding the higher radiation exposure of 18 FDG PET/CT in comparison to PET standalone, especially in oncologic patients who will undergo repetitive scans for tumor followup. Tipically, a PET scan with 370 MBq (10mCi) of 18 FDG delivers a dose of approximately 11 mSv to a patient, predominantly owing to the positrons emitted from isotopes. This dose is comparable to that of a diagnostic CT, ranging from 10 to 20 mSv. With the use of a CT scan for attenuation correction and anatomic coregistration the patient receives an additional dose that will vary depending on the quality of the CT scan and the protocol used: lowdose unenhanced-CT (LD-CT), full-dose contrastenhanced-CT (FD-CT). A LD-CT with 40 mAs adds approximately 2 to 8 mSv, resulting in a fi nal dose of 13-20 mSv for an integrated LD-18 FDG PET/CT study, which is similar to a diagnostic contrast-enhanced CT. A LD-18 FDG PET/CT performed with 40-80 mAs yields an adequate image quality and may suffi ce for many, though not for all, 18 FDG PET/CT oncologic applications (see below) (Brix et al. 2005;Kneifel et al. 2003). Nevertheless, the risk-benefi t ratio has to be taken into account in the individual patient, as correct diagnosis, staging and restaging are essential for an optimised and individualised therapy.

Major Indications of 18 FDG PET/CT in Oncology
Solitary pulmonary nodule (SPN) 18 FDG PET/CT helps characterize SPN, as most of malignant nodules show increased glucose metabolism (Fig. 4). The diagnostic accuracy of 18 FDG PET depends on the size of the nodule and its avidity for 18 FDG, and false-negative studies have been reported in nodules smaller than 1 cm, well-differentiated adenocarcinoma, bronchialveolar cell carcinoma, and carcinoid (Higashi et al. 1998;Gould et al. 2001). False-positive fi ndings include infectious and infl ammatory processes such as tuberculosis (Fig. 5), fungal infections, and sarcoidosis. It has been reported that 18 FDG PET/ CT can reliably characterize SPN Ն 7 mm (sensitivity 97%, specifi city 85%, overall accuracy 93%) (Kim et al. 2007), providing valuable information to guide patient management, especially useful where biopsy is risky, in elderly patients, or when there is a low risk for malignancy. This, SNPs with increased 18 FDG uptake are likely malignant and should undergo further invasive resection or biopsy. However, nodules PET negative still need to be followed (usually by CT) because of the possibility of false-negative PET fi nding (Christensen et al. 2006).

Non-small cell lung cancer (NSCLC)
18 FDG PET/CT has an important role in the initial staging, restaging, and in radiotherapy planning. Advantages of combined 18 FDG PET/CT over its isolated components in NSCLC evaluation include: better lesion identifi cation and localization, higher detection rate of lesions with low 18 FDG affi nity, and depiction of tumoral infi ltration in small lymph nodes. 18 FDG PET/CT has been reported to be the most accurate imaging technique in staging NSCLC, with accuracies for tumor (T), nodal (N) and metastases (M) staging of 70%-97%, 78%-93% and 83%-96% respectively (Lardinois et al. 2003;Sachelarie et al. 2005). The most important benefi t of the integrated modality relates to T staging, where 18 FDG PET/CT is clearly superior to either of its constituents, mainly due to the precise anatomic localization of the 18 FDG uptake (Lardinois et al. 2003;Halpern et al. 2005;Shim et al. 2005). Thus, CT improves depiction of focal chest wall  . 68 year-old woman that presented with a pulmonary node at chest radiograph. A nodule with pleura tail and increased 18 FDG uptake is observed in the right upper lobe at 18 FDG PET/CT scan. The histologic study demonstrated tuberculoma. and mediastinum infi ltration and vascular invasion (Lardinois et al. 2003), whereas PET is useful in differentiating tumor from post-obstructive atelectasis (Fig. 6) and characterizing pleural effusions as malignant (Schaffer et al. 2004;Lavrenov et al. 2005;Devaraj et al. 2007). It should be stressed the need to perform a diagnostic CT with intravenous iodinated contrast material in order to achieve a precise defi nition of tumor extension, distinguish contiguity of tumor and mediastinum from the direct invasion of the walls of mediastinal structures, and depict vascular invasion (Lardinois et al. 2003;von Schulthess et al. 2006;Pfannenberg et al. 2007). This is of utmost importance for both, planning of 3D conformal radiotherapy and extended non-conventional surgery. Recently, Pfannenberg et al. found that contrast-enhanced PET/CT more accurately assessed the TNM stage in 8% of patients with advanced NSCLC compared with non-contrast PET/CT, and showed signifi cant additional fi ndings in 20%. They suggest that contrastenhanced PET/CT should be performed in all patients with NSCLC who are primarily considered for local therapy such as surgery, neoadjuvant radiochemotherapy or definitive radiotherapy (Pfannenberg et al. 2007). Although PET/CT also has a higher diagnostic accuracy than either CT or PET alone for N staging (Lardinois et al. 2003), the improvement with respect to PET alone is more modest. The benefi t lies in a higher specifi city of PET/CT attributed to the precise anatomic information provided by the CT component. This is particularly useful for localization of lymph node metastases in patients with a mediastinal shift of with small solitary nodes that could be diffi cult on PET alone (von Schulthess et al. 2006). 18 FDG PET and 18 FDG PET/CT have a high negative predictive value for nodal involvement, greater than 90% (Pieterman et al. 2000;Schrevens et al. 2004, Pozo-Rodríguez et al. 2005. However, falsenegatives due to micrometastases ("minimal N2 disease") can occur in up to 8% of patients, although these patients have a better prognosis (Schrevens et al. 2004). The value of 18 FDG PET/ CT in nodal staging is limited by the low positive predictive value caused by infl ammatory changes in lymph nodes, especially in geographic areas with a high prevalence of granulomatous disease. For this reason, it is necessary to obtain histologic confi rmation of positive lymph nodes that would preclude surgery (De Langen et al. 2006). 18 FDG PET performs well at depicting extrathoracic metastases and detects unsuspected metastases in up to 28% of patients with NSCLC (Eschmann et al. 2002;Lardinois et al. 2003) (Fig. 7). The CT component provides exact localization of the PET fi ndings as well as complementary morphologic information that is especially useful in cases of doubtful adrenal lesions. In this regard, measurement of the Hounsfi eld Units of the lesion on the non-enhanced CT images (which are usually available) with the possible addition of a delayed enhanced CT at the end of the exploration may help characterize doubtful lesions, such as adenoma depicting 18 FDG uptake (Elaini et al. 2007;Metser et al. 2006;Pfannenberg et al. 2007).
On the other hand, it should be noted that 18 FDG PET/CT is not a sensitive technique for the detection of brain metastases because of the diffi culty in depicting 18 FDG-avid lesions in the physiologically hypermetabolic brain parenchyma (Bruzzi et al. 2006;Devaraj et al. 2007). For this reason, further imaging with brain MRI may be needed.
18 FDG PET/CT also has a signifi cant value in the assessment of suspected relapse, being particularly useful in cases with postherapy anatomic distortion (Keidar et al. 2004).

Colorectal cancer
Although considered potentially useful in the diagnosis and initial staging of colorectal cancer, currently there is no evidence of the superiority of 18 FDG PET/CT over standard diagnostic work-up (Pelosi et al. 2007). However, 18 FDG PET/CT has proven extremely useful in the assessment of patients with suspected recurrence. Early detection of recurrent disease is essential to perform an optimal salvage treatment and improve survival. Evaluation with CT of these patients is limited by its inability to differentiate between post-surgical or post-radiation scar tissue and recurrent disease, and to detect tumoral infi ltration of normal-sized lymph nodes. This is particularly true for the evaluation of post-treatment presacral masses, which occur in an elevated proportion of patient and poses a clinical challenge (Fig. 8).
18 FDG PET is very helpful in characterization of inconclusive lesions on morphologic imaging techniques, with reported diagnostic accuracies ranging from 74% to 95% as compared with 65% to 78% for CT (Schiepers et al. 1999;Huebner et al. 2000;Schaefer et al. 2007). 18 FDG PET is also useful to localize occult metastatic disease in patients with rising tumor marker levels and negative conventional imaging tests, and identify unsuspected metastases in up to 25% of patients (Pelosi et al. 2007). There are limitations to PET, however. The lack of anatomic landmarks probably accounts for its relatively low specifi city (76%) (Huebner et al. 2000), the false-positive interpretations of physiologic 18 FDG uptakes in pelvis with post-treatment anatomic distortion (Even-Sapir et al. 2004), rendering it unsuitable for guiding biopsy, surgery of radiation. In addition, lesions below its spatial resolution (6mm) and those with low 18 FDG uptake, such as mucinous adenocarcinomas can be missed on PET (Kamel et al. 2004). Many of these drawbacks are overcome with 18 FDG PET/CT. Several studies show the superiority of the combined modality in the detection of local recurrence of colorectal cancer, with sensitivities, specifi cities and diagnostic accuracies of 96%-100%, 96%-97% and 93%-96% respectively (Even-Sapir et al. 2004;Selzner et al. 2004;Schöder H et al. 2004;Votrubova et al. 2006;Pelosi et al. 2007). In a prospective study by Selzner et al. (Selzner et al. 2004) evaluating contrast-enhanced CT and unenhanced 18 FDG PET/CT in metastatic colorectal cancer, both modalities yielded comparable sensitivities for the detection of liver metastases (95% and 91% respectively), but 18 FDG PET/CT was superior for the diagnosis of intrahepatic recurrence after hepatectomy (50% versus 100%, p = 0.04), and extrahepatic disease (sentivities 64% and 89%, p = 0.02). Overall, 18 FDG PET/CT has been reported to change therapeutic approach in up to 26% of patients with recurrent colorectal cancer (Selzner et al. 2004;Votrubova et al. 2006).
Despite the high accuracy, false-positive and false-negative fi ndings may be encountered at 18 FDG PET/CT. Post-surgical and post-radiation infl ammatory tissue take up 18 FDG. For this reason, 18 FDG PET/CT imaging should be delayed until 2 to 3 months after completion of these treatments. Conversely, 18 FDG PET/CT performed within one month of chemotherapy may yield false-negative results because neoplastic tissue might not be metabolically active. 18 FDG PET/CT may not detect small lesions (Ͻ 5 mm) (Von Schulthess et al. 2006).
In addition, 18 FDG PET/CT, particularly when performed only with unenhanced LD-CT, may nor suffi ce when resection of liver metastases is being considered. In these patients, further imaging with hepatic MRI of dual-phase contrast-enhanced multidetector-CT is usually required in order to improve lesion detection and provide adequate anatomic information.
To summarize, 18 FDG PET/CT is extremely useful in the evalution of patients with suspected relapse of colorectal cancer, especially in cases with elevated carcinoembryonic antigen (CEA) and negative, equivocal or non-specifi c fi ndings on conventional imaging techniques, and to characterize post-therapy presacral masses. Currently, 18 FDG PET/CT is not indicated for screening or primary diagnosis or in patients with known diseminated disease. Promising uses of 18 FDG PET/ CT are monitoring chemo-radiotherapy and planning target volume in radiotherapic treatment (Ciernik et al. 2005;Pelosi et al. 2007).

Lymphomas
Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) are lymphoid neoplasias that have an elevated overall cure rate with current treatment modalities. Accurate staging is crucial for and adequate selection of therapy, and imaging plays an important role in the assessment of these patients. Enhanced CT has been the main modality used for staging and follow-up, but it is inaccurate for detecting involvement of normal-sized lymph nodes, spleen and bone marrow, and to exclude disease in post-therapy residual masses or enlargednodes. 18 FDG PET is now widely used for staging and restaging of HL and agressive NHL, and has superseded gallium-67 scintigraphy as the modality of choice for metabolic imaging of these patients. Despite its high sensitivity and specifi city, 18 FDG PET has limitations related to the absence of anatomic precise localization of lesions, the non-specifi c 18 FDG physiological uptake in some organs or in benign lesions, and the variable 18 FDG avidity of several histologic types.
Current data in the literature suggest the improved performance of 18 FDG PET/CT for staging and restaging of lymphomas as compared with contrast-enhanced CT (Freudenberg et al. 2004;Schaefer et al. 2004) and 18 FDG PET alone (Allen-Auerbach et al. 2004), yielding a sensitivity of 91%-94% and a specifi city of 88%-100%. 18 FDG PET/CT precisely locates tracer activity to a specifi c organ or node, reducing the false-positive fi ndings on 18 FDG PET standalone scans, and facilitates the identifi cation of sites of extranodal disease (Freudenberg et al. 2004;Schaefer et al. 2004;Schöder et al. 2004). 18 FDG PET/CT has been reported to change the stage in up to 10% and 32% of patients as compared with 18 FDG PET and CT respectively, and to alter patient management in up to 25% (Allen-Auerbach et al. 2004;Freudenberg et al. 2004;Raanani et al. 2006;Hernández-Maraver et al. 2006;Miller et al. 2006).
Probably, the most powerful application of 18 FDG PET/CT in lymphomas is the post-therapy assessment, especially in patients with residual masses, enabling characterization as either fi brosis or viable lymphoma (Fig. 9). It allows earlier detection of residual or recurrent disease. In order to avoid false-positives caused by post-therapy infl ammation, it is recommended to perform 18 FDG PET/CT at least 3 weeks after chemotherapy, and 8-12 weeks after completion of radiation therapy (Juweid et al. 2007).
There is also evidence that mid-treatment 18 FDG PET and 18 FDG PET/CT are useful as prognostic indicators for disease-free and overall survival in HL and aggressive NHL, as early as after 1-3 cycles of chemotherapy (Jerusalem et al. 2000;Kostakoglu et al. 2002;Schot et al. 2003;Schaefer et al. 2007). Early identifi cation of the patients who will not be cured with primary chemotherapy allows a change from a potentially toxic unsuccessful therapy to a more effective one. However, because of the false-positives that may result from post-chemoradiotherapy, and the morbidity and mortality associated with salvage treatments (including stem cell transplant), biopsy of the 18 FDG-avid lesions is still needed (Schaefer et al. 2007). Other signifi cant pitfalls regarding false-positive FDG uptakes after treatment include: opportunistic infections, thymic hyperplasia following chemotherapy, and bone marrow hyperplasia caused by colony-stimulating factor administration.
Thus, 18 FDG PET/CT seems to be valuable to taylor therapy by separating subgroups of patients with worse prognosis who will benefi t from different schemes of treatment, such as additional radiotherapy to areas of bulky disease or myeloablative chemotherapy followed by stem cell transplantation. Occasionally, 18 FDG PET/CT may identify localized recurrence or residual disease that could be treated with radiation therapy.
False-negative fi ndings have been described with lesions less than 1 cm, especially in the bases of lung, with small lesions in the liver or brain and mucosa-associated lymphoid tissue (MALT) NHL, because of the high 18 FDG uptake in surrounding tissues, and also with low-grade lymphomas showing a low 18 FDG uptake. In this regard, it is important to be aware of the histologic type of lymphoma when interpreting a 18 FDG PET/CT. Although there exists considerable overlap in the intensity of 18 FDG uptake, indolent lymphomas usually show lower 18 FDG avidity than aggressive ones (Elstrom et al. 2003;Schöder et al. 2005). HL, difuse large B cell (DLBCL) NHL, and follicular lymphoma are consistently 18 FDG avid. Conversely, peripheral T-cell, MALT, and small lymphocytic lymphoma exhibit variable, generally low 18 FDG avidity, and may not be detectable on 18 FDG PET scans. In this setting, the enhanced CT component of 18 FDG PET/CT adds valuable information, and facilitates detection of low-intensity 18 FDG uptake within lymph nodes or other lesions (Allen-Auerbach et al. 2004). On the other hand, 18 FDG PET/CT may be useful in patients with low-grade NHL as an indicator of histologic transformation into a more aggressive disease (Schöder et al. 2005). If an unexpected increase in the intensity of 18 FDG is detected in sites of disease with previously documented low uptake, 18 FDG PET/CT may direct biopsy to such lesions in order to confi rm transformation into a high-grade NHL.
Finally, the optimal protocol of 18 FDG PET/CT for lymphomas is not yet determined. There is controversy as to the necessity of performing the CT component with intravenous iodinated contrast material (Schaefer et al. 2004;Raanani et al. 2006). Our own initial results (Rodríguez-Vigil et al. 2006) show a good correlation between unenhanced low-dose 18 FDG PET/CT (LD-18 FDG PET/CT) and contrast-enhanced full-dose 18 FDG PET/CT (FD-18 FDG PET/CT) for lymph node and extranodal disease, suggesting that LD-18 FDG PET/CT might suffi ce as the only imaging modality in most patients with lymphoma, reducing contrast toxicity and radiation exposure. FD-18 FDG PET/CT could be reserved for selected cases such as those with liver or splenic involvement. One approach could be to perform FD-18 FDG PET/CT at initial staging and, unless the study shows 18 FDG PET-negative lymphoma or hepatic or splenic involvement, continue performing LD-18 FDG PET/CT on follow-up (Rodríguez-Vigil et al. 2006;Juweid et al. 2007).

Malignant melanoma
Malignant melanoma has the potential to metastatize anywhere in the body, including unusual sites such as myocardium, meninges, and gastrointestinal tract, and shows one of the highest 18 FDG uptakes of all tumors. For these reasons, wholebody 18 FDG PET has been proven to be highly effective for staging patients with high-risk melanomas (Eigtved et al. 2000;Tyler et al. 2000). However, metastases with no or weak 18 FDG PET uptake may occur (Aquino et al. 2006). In addition the value of 18 FDG PET imaging is limited for the depiction of metastases in the brain due to the high background activity of surrounding tissue, of small metastases, particularly in the lung, and of the necrotic lymph node metastases. The integrated 18 FDG PET/CT modality avoids some of these false-negative fi ndings at 18 FDG PET. The diagnostic accuracy of PET/CT has been shown to be signifi cantly higher than that of PET alone and CT alone for M-staging (0.98 vs 0.93 and 0.84 respectively), and signifi cantly higher than that of CT for N-staging (0.98 vs 0.86), leading to a change in treatment in 48.4% of patients (Reinhardt et al. 2006). In a recent prospective study, Strobert et al. (Strobert et al. 2007) found that the added CT information improved the overall accuracy of integrated 18 FDG PET/CT for depiction of melanoma metastases as compared with the readout on the basis of 18 FDG PET information alone (96% vs 91%, p = 0.016). In 13% of patients metastases were detected only by using coregistered CT, especially metastases in the lung with no 18 FDG accumulation.
18 FDG PET/CT has become the standard diagnostic tool for patients with high-risk melanoma (Breslow thickness Ͼ1.5 mm or know metastases). On the other hand, 18 FDG PET is less useful in patients without nodal or distant metastases (stage I-II) because of the higher sensitivity of sentinel node biopsy for detection of microscopic nodal metastases (Havenga et al. 2003).

Head and neck tumors
Conventional imaging of head and neck tumors with CT and MRI that rely on morphologic changes is limited by their insensitive to detect metastases in normal-sized lymph nodes and early recurrences due to the post-therapy anatomic distortion and persistent contrast enhancement of benign tissue. Serial imaging is often needed to confi rm stability of the lesion, suggesting scar or to evidence interval growth, indicating residual or recurrent disease, with a considerable delay in diagnosis and treatment. 18 FDG PET has a higher sensitivity than MRI/CT, but the poor spatial resolution in this complex anatomy of the head and neck, and the variable physiologic uptake of 18 FDG in normal structures such as muscles, brown fat, salivary glands, and the lymphoid tissue in the Waldeyer ring reduce its specificity and effectiveness Fukui et al. 2005).
Enhanced 18 FDG PET/CT has been reported to be superior to 18 FDG PET or CT alone for the evaluation of malignancy in the head and neck, with overall sensitivity, specifi city, and accuracy of 98%, 92% and 94%, against 74%, 75% and 74% of CT, and 87%, 91% and 90% of 18 FDG PET respectively. 18 FDG PET/CT showed an excellent negative predictive value (99%) (Branstetter et al. 2005). In a recent report, 18 FDG PET/CT led to a TNM staging alteration in 34%, a change in radiotherapy planning technique and/or dose in 29%, and altered therapy response assessment in 43% of patients with squamous cell carcinoma of head and neck (Connell et al. 2007).
Indications of 18 FDG PET/CT for head and neck cancer include: identifi cation of unknown primary, initial staging for the tumor, nodes, and metastases, and detection of residual or recurrent disease after therapy (Funki et al. 2005;Hojgaard et al. 2007). It is also emerging as the method of choice for radiation therapy planning (Hojgaard et al. 2007). 18 FDG PET/CT may be helpful in the search for a potential primary head and neck tumor in patients presenting with cervical metastatic adenopathies, and may direct biopsy in a second endoscopy. It has been reported that 18 FDG PET/CT suggests the primary site in up to 68% of patients with unknown primary tumors (Gutzeit et al. 2005;Nanni et al. 2005;Wartski et al. 2007). 18 FDG PET/CT allows a better depiction of the extent of the primary tumor, providing valuable information for the surgeon and/or radiotherapist. For regional nodal staging the main advantages of integrated 18 FDG PET/CT are the ability to detect metastatic infi ltration in normal-sized lymph nodes and better lymphadenopathy localization. In a recent study 18 FDG PET/CT was superior to 18 FDG PET and CT alone for predicting metastatic nodes on a levelby-level analysis (sensitivity 91.8%, specifi city 98.9%, and accuracy 97.1%), and also for the pathological nodal classifi cation (accuracy 85.1%) (Jeong et al. 2007). An additional advantage of performing whole-body 18 FDG PET/CT is that it allows screening for distant metastases and synchronous second primary cancer. Although distant metastases are uncommon in head and neck cancers it is important to detect them because a large number of patients will receive loco-regional treatment only (surgery and/or radiation therapy). Second primary tumors are relatively frequent in this population, particularly lung and esophageal carcinomas because of the common risk factors for these neoplasias von Schulthess et al. 2005) (Fig. 10). In patients with early and advanced stage primary head and neck squamous Figure 10. Synchronous lung cancer in a patient undergoing initial staging for laryngeal squamous carcinoma. 10A: axial contrast-enhanced CT (A), axial PET (B) and fused axial 18 FDG PET/CT (C) images at the level of vocal cords show a mass with intense 18 FDG uptake in the larynx consistent with laryngeal carcinoma. A focus of increased tracer activity is also identifi ed in the right lung at the coronal PET scan (D). 10B: axial contrast-enhanced CT (A), PET (B), and fused 18 FDG PET/CT (C) images at the lung bases. A peripheral lung mass abutting the pleura with a rim of increased 18 FDG uptake is observed in the right lower lobe. cell carcinoma 18 FDG PET/CT fi ndings led to a change in the treatment plan in 31% of patients, mostly by upstaging (Ha et al. 2006). Probably, the most important application of 18 FDG PET/CT in head and neck cancer is the assessment after treatment. Current data show a better performance of 18 FDG PET/CT than either 18 FDG PET or CT for detection of recurrent disease with sensitivities around 95%, and specifi cities of 60% Fakhry et al. 2007). 18 FDG PET/CT enables earlier detection of recurrences and with greater radiologists confi dence than with CT alone .
There are some limitations of 18 FDG PET/CT in evaluating head and neck cancers. It is important to take into account the interval of time between 18 FDG PET/CT and chemo-radiotherapy, as both, false-positive and false-negative fi ndings have been reported when performed within 3 months of treatment. The optimal timing for post-therapy reevaluation is debatable, but it has been suggested that 18 FDG PET/CT be performed at least 8-12 weeks after initial surgery or chemo-radiotherapy in order to obtain a more reliable malignancy status evaluation (Hojgaard et al. 2007). The sensitivity of 18 FDG PET/CT decreases for tumors smaller than 1 cm, especially fl at mucosal lesions or those near normal structures displaying physiologically high 18 FDG accumulation (brain, tonsils). In addition, the 18 FDG uptake may be underestimated in small lesions owing to partial volume averaging with normal tissue and show apparentely benign values. On the other hand, some slow-growing salivary gland tumors (mucoepidermoid, adenoid cystic tumors), and spindle cell neoplasms may have a low avidity for 18 FDG and yield falsenegative results. Also lymph nodes with extensive necrosis may show low tracer uptake and cause false-negative fi ndings ).

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FDG PET/CT is also indicated in the staging and restaging of iodine-negative thyroid cancer: dedifferentiated papillary or follicular cancer (neoplastic cells lose their ability to accumulate iodine), and advanced Hürtle cell and medullary carcinoma (Schmid et al. 2003). 18 FDG PET/CT is also a useful imaging modality in the assessment of response to treatment and detection of relapse in other metabolically active cancers, such as musculoskeletal sarcomas, gastrointestinal stromal tumors and esophageal carcinomas. 18 FDG PET/CT has proved useful in the detection of metastases that can be unsual in appearance or in unexpected locations in patients with esophageal carcinoma (Bruzzi et al. 2007). It has been reported to be superior to PET or CT alone and change patient management in up to 22% by detecting nodal and organ metastases (Schöder et al. 2004;Weber et al. 2004).
Though well-differentiated hepatocellular carcinomas (HCC) do not consistently show increased 18 FDG uptake, 18 FDG PET/CT may be useful in patients with poorly differentiated HCC, particularly in depiction of distant metastases of posttherapy recurrence (Von Schulthess et al. 2006). Furthermore, it may have a role in the selection of liver transplantation candidates. Yang et al. (Yang et al. 2006) have found that 18 FDG PET was a good preoperative tool for predicting post-transplantation tumor recurrence in these patients.
Preliminary studies also suggest that 18 FDG PET/CT may be valuable for ovarian, cervical, and endometrial cancer (von Schulthess et al. 2006).
Other PET tracers more tumor-specifi c than 18 FDG are being explored for certain cancers. These new tracers depict amino acid metabolism, receptor density, tissue hypoxia, angiogenesis and apoptosis, and could prove valuable in tumors with low avidity for 18 FDG, such as prostate cancer. 18 F-choline and 18 F-ethyl coline may become useful in prostate carcinoma staging (von Schulthess et al. 2006). Amino acids labeled with radionuclides such as 11 C-methionine, 18 F-ethyl tyrosine, 18 F-fluoro-alpha-methyl tyrosine (FAMT) and 18 F-thymidine are markers of protein synthesis (Oriuchi et al. 2006). They are potentially more cancer-specifi c than 18 FDG as they do not accumulate in infl ammatory tissue, but are less sensitive for tumor staging. FAMT has shown promising results in detection of pancreas, liver and brain tumors (Inoue et al. 2001) because it does not show intense accumulation in these organs. Also, octreotide derivates and 18 F-DOPA are being investigated as markers of neuroendocrine tumors (von Schulthess et al. 2006).
To summarize, 18 FDG PET/CT has emerged as powerful imaging tool in clinical oncology due to the synergistic advantages of its components. It has become the new standard imaging modality for many types of cancer. Despite its benefi ts, 18 FDG PET/CT has recognized limitations, and some clinical questions remain open. Ongoing research programmes will probably cast light on these issues. In addition, the application of new PET tracers other than 18 FDG that target specifi c biological characteristic of various cancer cells holds promise for further improvements in the management of cancer patients.